Collagenous colitis was first described by Lindstrom as chronic watery diarrhea (Pathol. Eur. 11(1):87-89 (1976)). Collagenous colitis is characterized by collagen deposition, likely resulting from an imbalance between collagen production by mucosal fibroblasts and collagen degradation. Very little is understood, however, regarding the mechanism by which collagenous colitis results in secretory diarrhea.
The incidence of collagenous colitis is similar to primary biliary cirrhosis. This disease has an annual. incidence of 1.8 per 100,000 and a prevalence of 15.7 per 100,000, which is similar to primary biliary cirrhosis (12.8 per 100,000) and lower than ulcerative colitis (234 per 100,000), Crohn's disease (146 per 100,000) or celiac, disease (5 per 100,000). In patients with chronic diarrhea, about 0.3 to 5% have collagenous colitis.
In efforts to characterize the patients under study, sera and monocyte conditioned media (MCM) from patients with collagenous colitis have been assessed for their ability to stimulate fibroproliferation. Cytokine antibodies were used to characterize the fibroproliferative component of patient samples.
Previous studies have suggested that MCM samples obtained from patients with liver disease are capable of stimulating proliferation of fibroblasts (see Peterson and Isbrucker, in Hepatol. 15(2):191-197 (1992)). It has also been established that several genes involved in proliferation possess AP-1 binding sites, and thus would be expected to be susceptible to regulation by the immediate early genes c-fos and c-jun (see, for example, Schafer et al., in Biochem. Biophys. Res. Commun. 221:111-116 (1996) and Bamberger et al., in Proc. Natl. Acad. Sci. USA 93:6169-6174 (1996)).
In order to determine whether these immediate early genes are upregulated by MCM obtained from patients with liver disease, the effect of MCM from patients with liver disease was investigated. MCM exerts many effects due to PDGF (see, for example, Peterson and Isbrucker in Hepatol. 15(2):191-197 (1992) and Peterson and Tanton in Can. J. Gastroenterol. 10:S76 (1996)). Indeed, it has been established that PDGF itself stimulates proliferation of fibroblasts (see Peterson, T.C. in Hepatol. 17(3):486-49:3 (1993) and Peterson et al., in Immunopharmacol. 28:259-270 (1994). Thus, the question of whether PDGF upregulates the expression of c-fos and c-jun was addressed.
Prior studies have indicated that pentoxifylline inhibits PDGF and MCM stimulated proliferation (see, for example, Peterson, T.C. in Hepatol. 17(3):486-493 (1993), Peterson et al., in Immunopharmacol. 28:259-270 (1994) and Peterson and Neumeister in Immunopharmacol. 31:183-193 (1996)). The mechanism for this effect of pentoxifylline remains unclear, but does not appear to involve competing for the PDGF receptor or adenosine receptor activation (see Peterson, T.C. in Biochem. Pharmacol. 52:597-602 (1996)). One possible mechanism for the inhibitory effect of pentoxifylline on PDGF-stimulated proliferation is inhibition of PDGF post-receptor signalling. Thus, in accordance with the present invention, it was undertaken to determine if compounds such as pentoxifylline modified the effect of PDGF on immediate early gene expression.
Accordingly, there is a need in the art to achieve a better understanding of the mechanism by which compounds such as pentoxifylline are effective to treat diseases and conditions such as collagenous colitis. Based upon a more complete understanding of the mechanism by which such agents are effective for the treatment of collagenous colitis, it may be possible to apply this understanding to the development of new methods of treatment for a variety of indications which are in no way related to collagenous colitis as well as identifying additional compounds which could be employed to treat fibroproliferative diseases and conditions.